The lungs are located in the chest and are coned shaped, sponge-like, and highly elastic organs. The functions of the lungs include gas exchange, moisturizing the inhaled air, balancing the temperature of air to body temperature, and filtering harmful substances 8. The upper tract of the respiratory system includes the oral cavity, the nasal cavity, and the trachea 10. The lower tract of the respiratory system includes the lungs, bronchi, and alveoli 10. During Inspiration and expiration, the volume of the chest cavity is changed 10. The air enters into the trachea, bronchi, bronchioles and then enters the lungs 10. The exchange of gases occurs in the alveoli are very thinly walled, balloon-like structures 8. Each alveolus is surrounded by capillaries. A high concentration of dissolved oxygen in the alveoli than in the capillaries causes oxygen diffuses across the alveoli walls into the blood plasma in the capillaries 8. A high concentration of carbon-dioxide (CO2) in the blood causes in CO2 diffusing from the capillaries into the alveoli. Exhaled air contains approximately 16% oxygen and 4.5% carbon dioxide 8. Each lung is identified by the apex, lobes, and base. The left lung has two lobes and right lung has three lobes 8. The left lung is smaller than the right to accommodate the heart and other structures in the mediastinum 8.Origin of lung cancer
The site of origin of lung cancer refers to the type of tissue from which the cancer cells develops 11. Lung cancer is categorized into two groups by the site of origin named hilar and peripheral types 8. The majority of early cancers in the hilar region are squamous cell types, whereas most of early stage lung cancers in the peripheral areas are adenocarcinoma 12. Adenocarcinoma originates in glandular tissue 13. NSCLC adenocarcinoma and large cell carcinoma are present as nodules or masses and are located in the peripheral of the lungs 8. Squamous cell carcinoma is normally located in the central portion of the lungs and can be misdiagnosed as an atelectasis or pneumonia 8. Small cell carcinoma is presented in the mainstem bronchi and originated in the Kulchitsky’ cells of the bronchial epithelium 8.
Types of lung cancer
Uncontrolled cell growth in the lung forming clumps of tissue referred to as lung malignant tumors 8. Exposure to carcinogens may cause malignant changes to the lining epithelium of the bronchi of the lungs 14. Around 95% of all lung cancer cases are classified into two major histological types named non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC originate from epithelial cells, while SCLC originate from neuroendocrine-cells. Around 85% of lung cancer cases are NSCLC 15. There are three major subtypes of NSCLC named squamous, large cell, and adenocarcinoma 16 according to physical and chemical characteristics of tumor cells.
Squamous cell carcinoma starts in the larger breathing tubes but grows slower and it account for around 25% to 30% of NSCLC cases. Adenocarcinoma, the slower growing type starts near the gas-exchanging surface of the lung 17 and that account for around 40% of all NSCLC. Large cell carcinoma is accounts for 10-15% of NSCLC and is a fast growing form that grows near the surface of the lung 18. Large cell carcinoma are often poorly differentiated and metastasize early 19. SCLC, also called “oat cell carcinoma” is the less common form of lung cancer. Approximately 20% of all primary lung cancer diagnosed are small cell lung cancer. SCLC tends to start in the larger breathing tubes and progresses rapidly 14. SCLC is more sensitive to chemotherapy, but has a worse prognosis and is often metastatic at presentation 20. The overall prognosis for all non-small cell lung cancers is poor, with a five-year survival rate of about 15%. The higher survival rate can be seen when the cancer is detected and treated early. Survival rates after surgery vary. For those with stage I disease, the five-year survival rate is about 47% 21. For those with stage III disease, the five-year survival rate is 8% 21. Squamous cell carcinoma readily spreads to distant parts of the body 22. Exposure to carcinogenic agents can cause progressive changes in the lung cell from metaplasia to atypia and dysplasia, then developing into a carcinoma in situ and invasive cancer 23. Metaplasia is defined as a transformation of a mature differentiated cell type into a different mature differentiated cell type 24. Atypia is defined as an abnormality associated with a precancerous process 24. Dysplasia is typically an irreversible condition or change in the cell that is a precursor of invasive epithelial tumors 24.
Lung cancer incidence and mortality rates are higher in men as compared to women 14. The primary cause of lung cancer in men is due to smoking tobacco products, in particular cigarettes 25. In 2010, it is estimated that lung cancer account for 10% of all cancer deaths in male in Sri Lanka 7. For men, the deadliness of lung cancer in Sri Lanka peaks at age 50-64 years. Lowest age rate at 15-34 years. Women at the highest rate form lung cancer in Sri Lanka at age >65 years. The young age of lung cancer diagnose in women at age 35-49 years 7.
Tobacco smoking has been recognized as the leading risk factor for lung cancer and more than 90% of lung cancer cases are caused by tobacco smoking. Smokers have at least ten-time higher risk of developing lung cancer compared to those who never smoked 26. Factors of smoking influence lung cancer risk include the duration of smoking, number of cigarettes per day, an age of initiation, inhaling habit, types of tobacco products and time since quitting 26. Although smoking is the predominant risk factors for lung cancer, lung cancer develops in 15% of male and 53% of female never-smokers 27. Previous studies have reported that, lung cancer patients with never-smokers as being more likely to be women, having adenocarcinomas, and having less-differentiated tumors 27. Genetic and epigenetic alterations also differ with fewer changes overall. Tumors from never-smokers also have a unique and predominant profile compared to those from smokers, such as chromosomal gains at 16p, promoter hypermethylation of hMLH1 and hMSH2, and distinct mutations of major oncogenes and tumor suppressor genes. For example, compared to smokers, never smokers have fewer mutations in K-ras and tp53 genes, while with a higher rate of mutation in EGFR, results in a better response rate of EGFR tyrosine kinase inhibitors in never smokers 27.
Environmental and occupational exposure
Evidence shows that second-hand smoking is another risk of developing lung cancer. Radon is another environmental risk factor for lung cancer, which commonly released from construction material. Occupational asbestos exposure is another important risk factor for lung cancer. People who worked in an environment with asbestos fibers have much higher risk to develop and die from lung cancer. Moreover, the joint effect was observed for asbestos exposure to tobacco smoking. Other environmental risk factors include air pollutions, diesel exhaust, and arsenic. Certain forms of silica and chromium also show associations with lung cancer.
Cancer is a complex process which involves an initial damage of the genetic material and this leads to a mutation in the chromosomes 28. The mutations can be inherited or somatic and resulting in alteration of clone cells of the original cell. Several genetic and epigenetic mutations of tumor suppressor genes have been identified in lung cancer 29. Thomas et al have found that in 95% of SCLC and 40-70% of NSCLC, the most frequently encountered genetic alteration was p53. The p53 affects the G1 and G2 cell cycle regulation. The p53 mutation leads the formation of DNA adducts (abnormal piece of DNA bonded to cancer causing agent) as a response to the effects of smoking; this mutation inhibits the normal cell repair and is involved in carcinogenesis. A proto-oncogene, K-ras is another biomarker and forms DNA adducts when damaged; women are three times more likely than men to have the K-ras mutation; this mutation is associated with adenocarcinoma 29.
Diet and Micronutrients
Some of the dietary factors include fruits, vegetables, carotenoids, vitamin C, phenols, flavones, vitamin E, selenium, isothiocyanates, folate, fat, and alcohol may serve as a protector against lung cancer for men and women 14. 16-23% reduction in lung cancer risk (RR = 0.77; 95% CI 0.67-0.87; p=0.001) was observed for men and women that had an increased consumption of vegetables and fruits compared to study participants that had a limited intake of fruits and vegetables 30.
More recent signatures have given emphasis in the detailed analysis of the protective action of cruciferous vegetables. Cruciferous vegetables contain isothiocyanates, non-nutrient compounds found to be effective inhibitors of tumorigenesis. It has recently been shown that weekly consumption of cruciferous vegetables decreased lung cancer risk (OR = 0.78; 95% CI 0.64-0.96) as compared to men and women that consumed cruciferous vegetables less than monthly 31. One study was designed to analyze the relationship between dietary factors and lung cancer risk. Skuladottir et al have demonstrated that, inverse relationship between an increased intake of fruits, vegetables, and lung cancer risk. Men and women in the highest quartile of intake of fruits and vegetables showed a 35% lower risk of lung cancer as compared to individuals in the lowest quartile of fruits and vegetable intake 32. Apart from that, carotenoids have been identified as the possible micronutrients in fruits and vegetables that may decrease lung cancer risk 33.
Estrogen hormone has been reported to reduce lung cancer risk 34. Schwartz et al. recruited 214 women and 64 men to investigate the association between the estrogen receptor (ER) receptor status, subject characteristics, and survival with lung cancer risk. The lung tissue was analyzed for the presence of ER-alpha and ER-beta with immunohistochemistry. Lung tissue sample which obtained from tumor and normal tissue were negative for ER-alpha. ER-beta receptors were positive in 61% of the lung tumor samples (70% of the men and 58% of the women) and in 20% of normal tissue. Women with adenocarcinoma were less likely to have positive ER-beta tumors than males ((OR = 0.40; 95%CI = 0.18-0.89) 34.
Another recent study has reported that the inter-individual difference expression of gender specific ER-alpha impact carcinogen metabolism and mutation based on analysis of genome CYP1A1 and CYP1B1 genes 35.
Other risk factors
People with family history of cancer are at higher risk of developing lung cancer. First-degree relatives of lung cancer patients have higher risk and/or early onset of the disease. Evidence shows that persons, who received radiation therapy to the chest, or to other cancers, have an increased risk of developing lung cancer.
Clinical Signs and Symptoms
The diagnosis of lung cancer is difficult that the majority of lung cancer cases asymptomatic until the disease have progressed to an advanced stage 24. Lung cancer patients are usually diagnosed with advanced stage diseases, due to the late presentation of symptoms or lack of symptoms. Common clinical lung cancer symptoms include a new or a persistent cough, hemoptysis, chest pain, wheezing, hoarseness, shortness of breath, and repeated respiratory infections 24. The symptoms of lung cancer can change according to the tumor type and the metastases 11.
Collins, et al revealed that there have been epidemiologic changes in the lung cancer patient population including an increased number of females with lung cancer and differences in the age of diagnosis. The frequently presented histological lung cancer type for males and females has changed to adenocarcinoma 9. These factors could negatively impact the rate of early diagnosis of lung cancer. Approximately 30-40% of diagnosed lung cancer cases have symptoms of metastatic disease some of the most common organs that cancer spreads to are the liver, brain, bones, spinal cord, and adrenal glands.
The symptoms of the metastatic disease include bone pain, confusion, high alkaline phosphatase level, seizures, weakness, weight loss, nausea, vomiting, and palpable lymphadenopathy 9. Other than that, lung cancer metastasis can cause endocrine manifestations include Cushing’s syndrome and hypercalcemia 9. 10% of lung cancer metastasis cases display clinical symptoms of the skeletal system including digital clubbing and hypertrophic pulmonary osteoarthropathy 9. SCLC is radiographically recognized by lymphadenopathy or the swelling of the lymph nodes and tumor invasion of the mediastinum 11. A characteristic of small cell lung cancer is the tumor is seen in the hilum in approximately 78% of the cases. Patients with small cell lung cancer can present with paraneoplastic syndromes. Paraneoplastic syndromes are a collection of clinical signs and symptoms resulting from the byproducts of the tumor interrupting normal biological function 9. Some of the syndromes resulting from small cell lung cancer include Lambert-Eaton syndrome, inappropriate antidiuretic hormone, and ectopic adrenocorticotrophic hormone production 11.